Ep 4 receptor-associated protein regulates gluconeogenesis in the liver and is associated with hyperglycemia in diabetic mice

Sei Higuchi, Risako Fujikawa, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kenji Mishima, Keiichi Irie, Michihiro Matsumoto, Masayuki Yokode, Manabu Minami

Research output: Contribution to journalArticle

Abstract

Prostaglandin E 2 receptor 4 –associated protein (EPRAP) is a key molecule in suppressing inflammatory responses in macrophages. EPRAP is expressed not only in macrophages but also in hepatocytes; however, the role of EPRAP in hepatocytes has not yet been defined. To examine the physiological role of hepatic EPRAP in mice, we performed the glucose tolerance test and the hyperinsulinemic-euglycemic clamp in high-fat sucrose diet (HFSD)-fed wild-type (WT) and Eprap null mice. We evaluated the contribution of EPRAP to gluconeogenesis by pyruvate tolerance test and primary hepatocyte experiments. Furthermore, lentivirus-expressing Eprap-specific small-hairpin RNA was injected in db/db mice. HFSD-fed Eprap null mice had significantly lower blood glucose levels than HFSD-fed WT mice. Eprap null mice also had low glucose levels after fasting or pyruvic acid injection. Moreover, primary hepatocytes from Eprap-deficient mice showed decreased glucose production and lower expression of the Phosphoe-nolpyruvate carboxykinase and Glucose 6-phosphatase genes. Lenti-virus-mediated hepatic Eprap suppression decreased glucose levels and the expression of gluconeogenic genes in db/db mice. We conclude that EPRAP regulates gluconeogenesis in hepatocytes and is associated with hyperglycemia in diabetic mice. Our data suggest that suppression of EPRAP could be a novel strategy for the treatment of diabetes.

Original languageEnglish
Pages (from-to)E410-E417
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume316
Issue number3
DOIs
Publication statusPublished - Mar 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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